Obesity is a well documented risk factor for worse outcomes in acute pancreatitis (Martinez, et al., Pancreatology 2006, 6:206-209; Papachristou, et al., Pancreatology 2006, 6:279-285; Sempere, et al., Pancreatology 2008, 8:257-264; Karimgani, et al., Gastroenterology 1992, 103:1636-1640), including the risk of local complications (Tsai C J, Dig Dis Sci 1998, 43:2251-2254; Funnell, et al., Br J Surg 1993, 80:484-486), systemic complications such as the systemic inflammatory response syndrome (SIRS), multisystem organ failure (MSOF) and mortality (Papachristou, et al., Pancreatology 2006, 6:279-285; Karimgani, et al., Gastroenterology 1992, 103:1636-1640; Funnell, et al., Br J Surg 1993, 80:484-486; Johnson, et al., Pancreatology 2004, 4:1-6) and the risk of local complications. The sites of visceral fat deposition include the mesentery, omentum, liver (Park, et al., J Gastroenterol Hepatol 2008, 23:900-907), the pancreas, and the peripancreatic space (Olsen T S, Acta Pathol Microbiol Scand A 1978, 86A:367-373; Rosso, et al., J Gastrointest Surg 2009, 13:1845-1851; Saisho, et al., Clin Anat 2007, 20:933-942; Schmitz, et al., Pathol Res Pract 1981, 173:45-53). It has been suggested that visceral adipose tissue, as measured by waist-to-hip ratio and waist circumference above ideal cut-off value, may be a greater risk factor for worse outcomes in acute pancreatitis than total body fat (Mery, et al., Pancreatology 2002, 2:543-549; Martinez, et al., Pancreas 1999, 19:15-20). Mechanisms of this may include an elevated baseline proinflammatory state (Ghanim, et al, Circulation 2004, 110:1564-1571) and an exaggerated inflammatory response (Sempere, et al., Pancreatology 2008, 8:257-264) associated with obesity. Levels of proinflammatory cytokines such as Interleukin-1β and tumor necrosis factor-α are increased in pancreata of obese mice (Mathur, et al., Nonalcoholic fatty pancreas disease, HPB (Oxford) 2007, 9:312-318). Increased fat accumulation in the pancreas and peripancreatic space has been noted in association with increased body weight (Olsen T S, Acta Pathol Microbiol Scand A 1978, 86A:367-373; Saisho, et al., Clin Anat 2007, 20:933-942; Schmitz, et al., Pathol Res Pract 1981, 173:45-53).
Intrapancreatic fat has been shown to increase with BMI in studies evaluating autopsy samples (Olsen T S, Acta Pathol Microbiol Scand A 1978, 86A:367-373; Saisho, et al., Clin Anat 2007, 20:933-942; Schmitz, et al., Pathol Res Pract 1981, 173:45-53) surgically resected samples (Rosso, et al., J Gastrointest Surg 2009, 13:1845-1851) and radiological appearance of the pancreas (Saisho, et al., Clin Anat 2007, 20:933-942; Matsumoto, et al., Radiology 1995, 194:453-458). The distribution of fat is fairly uniform in the dorsal pancreas and is reduced in the ventral pancreas (Schmitz, et al., Pathol Res Pract 1981, 173:45-53). Uneven fatty replacement in the pancreas is infrequent (3.2%), and the pattern of fat distribution is not influenced by obesity (Matsumoto, et al., Radiology 1995, 194:453-458).
The pancreas produces enzymes that aid in digestion and absorption of food; one such enzyme is lipase, which digests fat. A number of inhibitors of pancreatic lipase, which can inhibit absorption of ingested fat and thereby reduce caloric intake, have been developed as anti-obesity drugs. Examples of pancreatic lipase inhibitors include orlistat (marketed as the prescription drug Xenical by Roche and as an over-the-counter drug, Alli, by GlaxoSmithKline), cetilistat, and lipstatin. Orlistat has been reported to promote apoptosis and reduce cell grown and lymph node metastasis in a mouse melanoma model (Carvalho et al., Int. J. Cancer 2008, 123:2557-2565).